This is a competing renewal for a project aimed at identifying the structural requirements for cannabinoid activity through the synthesis of novel ligands for the known cannabinergic sites. The goals of the current funding period included the CB1 and CB2 receptors and anandamide amidase as targets for our structure activity correlations and focused on three classes of cannabimimetic ligands, the classical and nonclassical cannabinoids (CCs, NCCs) and anandamide (AN). However, this intervening period has witnessed the discovery of the anandamide transporter (AT) and a second family of endogenous ligands represented by 2-arachidonyl glycerol (2AG) as well as the development of diarylpyrazole (PY) analogs as a new class of CB1 and CB2 antagonists. These developments have motivated us to widen the scope of this project by including the design and synthesis of 2AG and PY analogs and adding the AT as a target for our structure activity correlations. Our drug design encompasses three structural targets; a) the synthesis of novel later generation CCs and NCCs incorporating conformationally restricted pharmacophoric features and additional heteroatoms; b) novel conformationally more defined AN and 2-AG analogs; c) novel pyrazole analogs as later generation CB1 antagonists with improved pharmacological properties. We shall study the stereoelectronic properties of the most successful novel cannabinergic agents both in solution and in the membrane using high resolution NMR as well as theoretically using molecular mechanics and molecular dynamics. Furthermore, the nature of the ligand-receptor interaction will also be explored on three dimensional computer models of CB1 and CB2 receptors. All analogs will be tested for their affinities and functional properties (as agonists, antagonists, and inverse agonists) with regard to CB1 and CB2 in membrane preparations and in whole animals. The AEA and 2AG analogs will also be tested for their effectiveness in inhibiting anandamide amidase and the anandamide transporter. The long term therapeutic targets of the project include the development of (a) therapeutic agents for nicotine, opioid, alcohol or cocaine addiction; (b) non-opioid analgesics devoid of the known psychotropic properties of cannabinoids.